It is now well accepted that obesity and diet induce inflammation in adipose tissue (AT) and that this may promote the development of systemic insulin resistance. It is currently believed is that obesity/diet-induced AT inflammation is predominantly driven by macrophages that produce pro-inflammatory mediators. However, we speculate that adipocytes themselves may also participate in the process. Indeed, it is possible that they even initiate AT inflammation by stimulating macrophage recruitment and activation. Supporting this notion is our discovery that adipocytes undergo significant changes in response to a high fat diet that take place before macrophage infiltration and systemic insulin resistance are observed. Furthermore, we found that when only adipocytes are constitutively inflamed in mice, AT infiltration by macrophages and macrophage activation are observed along with the spontaneous development of systemic insulin resistance. These observations clearly suggest that adipocytes may play an important role in mediating the obesity/diet-induced inflammatory processes that lead to the development of systemic insulin resistance. In addition, our immunohistological analyses have revealed that only some adipocyte sub-populations interact with the AT-infiltrating macrophages, with the majority of adipocytes being free of contact with macrophages. This suggests that these adipocyte sub-populations may be focal adipocytes that initiate AT inflammation. Taken together, these results led us to hypothesize that 1) AT is composed of heterogeneous adipocyte populations, 2) adipocyte sub-populations are inflamed by obesity and diet in an NF:B-dependent manner and go on to initiate AT inflammation (including macrophage infiltration and activation), and 3) activation of AT inflammation promotes inflammation-induced systemic insulin resistance. We will test these hypotheses by using a newly developed large particle sorter to identify and characterize the adipocyte sub-populations that may be responsible for obesity/diet-induced inflammation. We will also determine the effect of specifically suppressing or activating adipocyte inflammation on the macrophage responses to obesity/diet by using tissue-specific knock-out or transgenic mice. The converse situation, namely, how specifically suppressing macrophage inflammation affects adipocyte responses to obesity/diet, will also be examined. The information generated by these experiments will greatly improve our understanding of the role adipocytes play in inducing inflammation and insulin resistance. It will also provide insights into how adipocytes and macrophages interact with each other in AT to regulate their own inflammation and function, and how these interactions ultimately lead to obesity/diet-induced insulin resistance. [unreadable] [unreadable] PUBLICH HEALTH RELEVANCE STATEMENT: We have recently found that low-grade inflammation in fat tissue induce the development of insulin resistance. In this application, we tried to find how fat cells regulate induction of inflammation by obesity and diet. The findings from this application may help us to find molecular targets for the treatment of insulin resistance and Type 2 Diabetes. [unreadable] [unreadable] [unreadable]